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Playing with Blocks

While Evans and others are working on machines that could expand researchers’ ability to write genes, chemists at the Scripps Research Institute in La Jolla, CA, are expanding the genetic alphabet itself. “Our repertoire of bases is naturally limited,” to the familiar DNA letters A, T, C, and G, says Scripps chemist Floyd Romesberg. Because these letters tell an organism which proteins to make, the types of proteins that can be specified by the genome are limited as well. Getting, say, a bacterium to make novel types of proteins would require adding new DNA letters.

That’s exactly what Romesberg’s lab has done. Building on the pioneering work of biologist Steven Benner at the University of Florida, Romesberg and his colleagues have created a letter in the form of the chemical fluorobenzene. This artificial DNA letter looks nothing like a natural one, he says, so the challenge is to trick the cell’s DNA replication and translation machinery into recognizing it. So far, the Scripps researchers have synthesized short fragments of DNA that incorporate the new letter and have successfully created an enzyme that can replicate the modified code. The next step is to design a system for translating the code into a completely unnatural protein-a novel drug, for instance.

To do this, Romesberg is collaborating with another Scripps chemist, Peter Schultz. While Romesberg’s team was rejiggering the DNA alphabet, Schultz’s lab was tinkering with another set of biological building blocks: the amino acids that form proteins. Living things use 20 amino acids, which are strung together as proteins, following instructions encoded in the DNA. Schultz’s group created a bacterium that has 21, the 21st being a chemically modified version of a natural amino acid. Such synthetic amino acids offer the chance to build new functions into proteins. “There’s a huge range of chemical groups that we could put into proteins to make them do interesting things,” says Schultz. He is, for instance, working on creating photosensitive amino acids which, in response to light, could trigger specific reactions in a cell.

What’s more, the two Scripps teams are working to combine their techniques. The goal: to create cells with all the enzymes and other molecules necessary to translate DNA code that bears Romesberg’s artificial letter into proteins that incorporate Schultz’s artificial amino acids. The technology could have a huge impact on the development of new protein therapeutics, says Schultz. Protein drug researchers typically modify natural proteins-adding a specific sugar that binds to a cancer cell, for example-to increase their effectiveness. “But what these people are doing is kind of dirty chemistry,” says Schultz. Treating these extra chemical groups as artificial amino acids and directly encoding them in a synthetic gene would enable researchers to modify proteins with incredible selectivity and simultaneously create living factories that churn out the new proteins.

“We’ve removed a billion-year-old constraint on what we can do with proteins,” says Schultz. “And so we’re taking the point of view that if God had worked on Sunday, and he had more amino acids to work with, what would have been the outcome?” Would an organism with an expanded genetic code and amino acid inventory have an evolutionary advantage? Perhaps there is a reason why all known organisms share those 20 building blocks. “Is it just a chance of history that early life took this route?” asks Stephen Freeland, an evolutionary geneticist at the University of Maryland, Baltimore County. “Or is there more to it?”

If scientists could answer such big theoretical questions, Freeland says, it might be possible one day to discover on other planets life that might not otherwise be recognizable. And if the synthetic-genome technologies in the works at Scripps, Egea, Venter’s institute, and elsewhere pan out, life right here on Earth could soon look a little less familiar-and a lot more diverse.

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Tagged: Biomedicine

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